Homeostasis refers to the ability of humans and other animals to maintain physiological parameters at relatively constant levels in the face of environmental flux. For example, even small departures from homeostatic levels of body temperature, hydration, osmolality, blood pressure, or oxygenation can have serious adverse effects on physiological and behavioral functioning. Fortunately, tight regulation of these and many other parameters is typically carried out automatically, often without conscious awareness of the bodily adjustments that serve to that preserve equilibrium. Walter B. Cannon (1932) referred to this type of automatic regulatory control as the "wisdom of the body (13)." The term energy homeostasis refers to the ability to regulate energy use and body weight at relatively constant levels despite local environmental variations in food availability or intake. For example, it is not unusual for people to indulge in large, energy-rich meals that provide calories well in excess of their short-term needs, eat smaller more "calorie conscious" meals on other occasions, and skip meals altogether at other times. The fact that many people maintain normal body weight over the long-term, despite such wide meal-tomeal fluctuations in energy intake, points to the existence of regulatory control mechanisms that enable people to compensate precisely for shorter term excesses (or deficits) with periods of decreased (or increased) caloric consumption. Unfortunately, it appears that this compensatory system is becoming increasingly ineffective, as data from several sources indicate that the proportion of the population classified as overweight or obese has climbed steadily since the mid-1980s. This increase has been documented across the lifecycle in both genders and among all ethnic groups (32, 67, 96). Moreover, a problem often overlooked is that for many normal weight people the ability to maintain body weight at constant level is no longer automatic. Rather, it often depends on careful adherence to self-imposed regimens of dietary restriction and exercise. Given the clear and serious implications of overweight and obesity for public health, it is critically important to identify factors that not only cause this type of dysregulation but are also capable of producing dysregulation on the massive scale that we are witnessing now. Much previous research has been directed at discovering the neural, hormonal, metabolic, and genetic controls of intake and body weight regulation. Although this work has provided much new information, the causes of obesity remain elusive, and compelling explanations about how changes in body physiology or genetics might produce the current obesity epidemic have not been forthcoming. The research proposed in this application approaches the problem from a different perspective. We suggest that the "wisdom of the body" involves the ability to use food cues (e.g., taste, texture, aroma, external cues that are associated with food) to anticipate the nutritive and caloric consequences of eating. By predicting the arrival of nutrients in the gastrointestinal tract, these cues evoke physiological responses that optimize utilization of these nutrients and also minimize their ability to perturb homeostasis (102). Over the last 25 years, increased incidence of overweight and obesity in the United States appears to be directly correlated with the intake of artificial sweeteners. The focus of our proposed research program will be to study the possibility that consumption of artificially-flavored, low- or no-calorie foods and beverages might function to "outwit" the wisdom of the body. This possibility is derived from what we think is a novel theoretical formulation that links the efficiency of the regulatory control of intake and body weight to a relatively simple form of Pavlovian conditioning. Within this framework, consuming sweet- or fatty-tasting substances which contain few or no calories has the effect of degrading the normal ability of sweet or fat orosensory cues to predict calories. As a consequence of weakening this predictive relationship, sweet- or fatty-tasting foods that contain calories become less able to evoke the compensatory physiological responses that underlie tight regulation. This model supplied the impetus for several preliminary studies. These studies provided initial evidence that the ability to regulate caloric intake and body weight is disturbed in rats that have a brief history of consuming artificially-sweetened or fat-substituted foods. Specific Aims 1-4 will attempt to further characterize this type of regulatory disturbance and the conditions under which it occurs. The final specific aim is to assess directly the hypothesis that consuming sweet-tasting but noncaloric substances interferes with the normal ability of sweet tastes to evoke anticipatory physiological responses that may contribute to energy homeostasis.